1. Alzheimers Disease: Three series of agents are being developed to treat AD. Selective inhibitors of amyloid-beta peptide (abeta) production and inhibitors of the enzymes acetylcholinesterase (AChE) and butrylcholinesterase (BChE) 1.1. Molecular events associated with AD: A reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as an important therapeutic goal in AD. Targets to achieve this goal are factors that affect the expression and processing of the Abeta precursor protein (APP). Our studies have generated compounds to reduce APP and Abeta levels in neuronal cultures and the brain of animal models without toxicity. This activity is independent of cholinergic action, but is post-transcriptional: lowering APP protein levels without affecting mRNA levels via translational regulation. This is mediated, in part, via the 5-untranslated region (UTR) of APP mRNA. Current studies are characterizing mechanisms involved and focusing on these in the design and synthesis of agents that lower APP levels as a way of lower Abeta peptide (collaborators: Drs. Lahiri, Sambamurti, Rogers). The compound, Posiphen, has advanced to clinical trials and backup compounds are being assessed to define molecular mechanisms underpinning activity. Posiphen has advanced to phase 1 clinical trials, appears well tolerated and effectively lowers APP levels and other important AD CSF markers (collaborator: Dr. Maccecchini). 1.2. Cholinesterase inhibitors: Compounds were developed to optimally augment the cholinergic system in the elderly and raise levels of the neurotransmitter, acetylcholine (ACh). Extensive studies involving chemistry, X-ray crystallography, biochemistry and pharmacology resulted in the design and synthesis of novel compounds to differentially inhibit either AChE or BChE in either the brain or periphery for an optimal duration for the potential treatment of a variety of diseases, such as AD, myasthenia gravis, and as chemical warfare prophylactics (collaborators: Drs. Becker, Lahiri, Kamal, Reale, Sambamurti, Shafferman, Descamp). In addition, specific and highly selective BChE inhibitors have been designed to characterize the role of this enzyme in brain during health, aging and disease. 1.2A. AChE: To develop long-acting, centrally active, selective inhibitors of the enzyme, AChE, to characterize its role in health and disease and to generate compounds of translational clinical potential, an extensive program of chemistry was developed on the template of the classical, short-acting, unselective anticholinesterase, eserine. Novel phenylcarbamates were developed that are 70- and 190-fold selective for AChE vs. BChE. They have a favorable toxicologic profile and robustly enhance cognition in animal models. They possess a long duration of reversible enzyme inhibition, coupled with a short pharmacokinetic half-life. This reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. In collaboration with industry, one of these novel agents, phenserine, translated from the laboratory and into clinical trials where actions on cognition and levels of CSF and plasma Abeta have been assessed in AD (collaborators: Drs. Becker, Nordberg, Friedhoff, Winblad, Sambamurti, Bruinsma). In clinical trials phenserine effectively improved cognition and modified CSF Abeta levels. Optimization of the formulation is being undertaken to support further clinical development (Collaborators, Drs. Becker, Chigurupati, Flanagan) 1.1B. BChE: In normal brain, some 80% of cholinesterase activity is in the form of AChE and 20% is BChE. AChE activity is concentrated mainly in neurons, while BChE is primarily associated with glial cells. Kinetic evidence indicates a role for BChE, in hydrolysing excess ACh. In advanced AD, however, AChE activity decreases to 15% of normal levels in affected brain regions, whereas BChE activity increases. The normal ratio of BChE/AChE becomes mismatched in AD causing excess metabolism of already depleted ACh. The first reversible, centrally-active potent BChE inhibitors have been synthesized and appear favorable in AD preclinical models. Bisnorcymserine was specifically chosen and has advanced through required preclinical studies and an IND has been approved for clinical studies. Additional studies are utilizing these valuable agents to define the role of BChE in brain in health, aging and disease (collaborators: Drs. Lahiri, Maccecchini, Kapogiannis, Kamal) 1.3. Utilizing the compounds generated above, the relationship between the cholinergic system and inflammation is being characterized in health and disease (collaborators: Drs. Reale, Kamal) 2. Stroke, Parkinsons disease (PD), brain trauma: Drugs currently used provide temporary relief of symptoms, but do not prevent the occurrence of cell death. Our target for drug design is the transcription factor, p53. Its up-regulation is a common feature of several neurodegenerative disorders, and is a gate keeper to the biochemical cascade that leads to apoptosis. We recently designed and synthesized a novel series of tetrahydrobenzothiazole and oxazole analogs that inhibit p53 activity. Compounds are in current assessment for neuroprotective action in tissue culture and animal models (collaborators: Drs. Pick, Hoffer, Wang) to select agents of potential for evaluation as drug candidates. Compounds of this class have demonstrated biological activity in cellular and/or animal models of stroke, AD and PD, and are being assessed in other neurodegenerative diseases to define their optimal use. 3. Inflammation: Inflammation is a critical feature of neurodegeneration and also occurs in numerous systemic diseases. Our target is the cytokine, TNF-alpha. Novel, potent TNF-alpha inhibitors are being synthesized on the template of thalidomide and revlimid. They reduce TNF-alpha synthesis post-transcriptionally, via its 3-UTR, in cell culture studies. These are being assessed in vivo to define time- and concentration inhibition of TNF-alpha systemically and in brain. Upto 90% inhibition can be achieved in either compartment. Classical animals models are be utilized to aid the selection of a clinical cadidate for chronic diseases such as amyotrophic lateral sclerosis, AD and PD, as well as head trauma (collaborators: Drs. Rosi, Bosetti, Pick, Hoffer, Wang, Ingram, Levis). 4. Clinical translation and assessment of experimental drugs in neuropsychiatric conditions: Despite promising advances in understanding possible mechanisms of disease in recent years, clinical investigators still struggle with methods and practices too open to effects from measurement errors, biases, carelessness at research sites distant from the sponsor, and with commercial pressures to as quickly as possible enter human trials - a priority that is acknowledged to allow frequently insufficient preclinical investigations and suspected as one cause for failures in human clinical trials. Hence, drug discovery/development is acknowledged as at great risks of failing due to lack of efficacy or compromises to safety. Less than 11% of all new agents that enter clinical development reach the marketplace (Kola & Landis, Nature Rev Drug Discov 3:711-5, 2004). For neurological drugs, attrition is considerably higher still, less than 7%. To understand and optimize clinical development the numerous factors that impair the process and generate type 2 errors are being critically reviewed and assessed (Collaborator: Dr. Becker). Rational approaches to optimize the clinical drug development process of neuropsychiatric drugs are being developed to aid reduce the currently too high attrition rate.